PROJECT SUMMARY/ABSTRACT Apathy is defined as a loss of will and initiative, lack of interest in activities, lack of productivity, as well as limited affective response to positive or negative elements . Apathy is one of the most common neuropsychiatric symptoms (NPS) of Alzheimer's disease (AD), affecting approximately 70% of AD patients and resulting in serious adverse consequences for patients and caregivers. Apathetic patients are also more likely to require institutionalization, the largest single driver of direct costs in AD. Despite the high prevalence of apathy in AD and its serious consequences, there are no proven treatments for this condition. Nonpharmacologic strategies appear to have limited effects on apathy in AD, as do current FDA-approved medications for AD such as cholinesterase inhibitors. Recently, new research has suggested the involvement of dopamine pathways in the biology of apathy in AD and the potential value of dopamine enhancers, such as methylphenidate, for the treatment of this condition. Moreover, we have recently reported the results of two six- week randomized controlled trials showing a clear benefit of methylphenidate over placebo in treating apathy in AD, as well as potential cognitive benefits of methylphenidate and a favorable safety/tolerability profile. [However, a number of key questions relevant for clinical practice were not answered by these studies. For example, is the treatment effective and safe beyond six weeks in a larger sample? Can the potential cognitive benefit of methylphenidate be reproduced and remain clinically significant in this population? Can the combination of a decrease in apathy and an improvement in cognition be translated to clinically significant functional change? Does the treatment of apathy in AD have an impact on subject quality of life and pharmacoeconomics? We propose to address these questions by conducting a multi-site, parallel, randomized, double-blind, placebo-controlled study evaluating methylphenidate for the treatment of apathy in AD patients (Apathy in Dementia Methylphenidate Trial-II (ADMET II)) in a larger sample, over a more extensive period of time and employing a concise battery of neuropsychological tests optimized for apathetic AD patients. The ultimate goal is to collect evidence strong enough to support a change in clinical practice. This trial will bring together a team of investigators who have collaborated successfully in the execution of the first ADMET study as well as other clinical trials exploring treatments for neuropsychiatric symptoms of dementia.]